Sulfur-based amides and bis-amides useful against skin disorders

ABSTRACT

Novel sulfhydryl group-containing amides and disulfide group-containing bis-amides useful for treating or preventing an abnormal biological condition or a disease, and/or improving the texture or appearance of the skin, as well as compositions containing amides and bis-amides and methods for their use are described. Such types of abnormal biological conditions or diseases include skin atrophy, i.e., the thinning and/or general degradation of the dermis often characterized by a decrease in collagen and/or elastin as well as decreased number, size and doubling potential of fibroblast cells, and other maladies including, but are not limited to dry skin, severe dry skin, dandruff, acne, keratoses, psoriasis, eczema, skin flakiness, pruritus, age spots, lentigines, melasmas, wrinkles, warts, blemished skin, hyperpigmented skin, hyperkeratotic skin, inflammatory dermatoses, age-related skin changes and skin in need of cleansers.

This is a division, of application Ser. No, 08/626,769, filed Mar. 29,1996, now U.S. Pat. No. 5,683,705.

1. FIELD OF THE INVENTION

This invention relates to novel sulfhydryl group-containing amides anddisulfide group-containing bis-amides useful for treating or preventingabnormal skin conditions or diseases, and/or improving the texture orappearance of the skin, to pharmaceutical or cosmetic compositionscontaining the sulfhydryl group-containing amides and disulfidegroup-containing bis-amides and to methods for the use of the compoundsand compositions.

2. BACKGROUND OF THE INVENTION

Hydroxybenzoic acids and α-hydroxycarboxylic acids (known as "AHAs")have been used to treat skin conditions for over several decades. Forexample, α-hydroxycarboxylic acids have been used to treat ichthyosis,hyperkeratoses, dandruff and acne (see, U.S. Pat. Nos. 3,879,537 to VanScott et al.; 3,920,835, 3,988,470, and 4,234,599 to Van Scott et al.;3,984,566 to Van Scott et al.; and 4,105,782 to Yu et al.;respectively). α-Hydroxycarboxylic acids have also been used to treatdry skin (see, U.S. Pat. Nos. 4,105,783 to Yu et al.; 4,194,007 to VanScott et al.; 4,197,316 to Yu et al.; 4,380,549 to Van Scott et al.;4,363,815 to Yu et al. and 5,091,171 to Yu et al. α-Hydroxycarboxylicacids have also been used to enhance the antiinflammatory action ofcorticosteroids (see, U.S. Pat. No. 4,246,261 to Van Scott et al.). U.S.Pat. No. 5,254,343 to Parah et el. discloses the use of salts ofα-hydroxyacids in conjunction with steroids to minimize cutaneousatrophy, a side-effect of steroid application to the skin. U.S. Pat. No.4,542,129 to Orentreich teaches the use of a mixture of a keratolyticagent, such as a hydroxybenzoic acid or an α-hydroxycarboxylic acid, anddehydroepiandrosterone to treat dry skin while deterring acne formation.

Salicylic acid has also been used to treat conditions of the skin.International Publication No. WO 93/10756, published Jun. 10, 1993 toBlank teaches the use of salicylic acid to regulate wrinkles and/oratrophy in mammalian skin. U.S. Pat. No. 5,262,407 to Leveque et al.teaches the use of C₁ -C₁₈ alkanoyl 5-acylsalicylic acids to treat agingskin.

One of the drawbacks of using α-hydroxyacids or hydroxybenzoic acids,such as salicylic acid, for treating persons having skin ailments,however, is that at high concentrations, such acids are known to removethe outer layer of skin by chemically burning the skin off the patient.Such treatments are known in the art as "chemical peels." However, whenimproperly monitored, chemical peeling of the outer layer of skin usingthese acids can lead to inflammation, infection and scarring. Inaddition, α-hydroxyacids are known to cause skin irritation at certainlower levels in some individuals. Thus, there is a need for acomposition capable of providing the skin-healing benefits ofα-hydroxyacids or hydroxybenzoic acids, such as salicylic acid, whileavoiding the drawbacks such as those described above.

Hydroxylated thioethers also been used to treat skin ailments. Forexample, U.S. Pat. No. 3,968,218 to Bouillon et al. discloses the use ofhydroxylated amino thioethers for treating greasy skin.

Cysteamine derivatives have been used on the skin and scalp. FR1,505,874 to Kalopissis discloses the use of S-benzylcysteamines for thetreatment of seborrhea and acne. U.S. Pat. No. 4,089,942 to Bore et al.discloses deodorant compositions for body hygiene comprisingS-benzylcysteamine or an organic salt thereof. U.S. Pat. No. 5,334,377to Junino et al. discloses the use of cysteamine amides of aminoacids asreducing agents useful in a process for the permanent deformation of thehair. None of the above references suggest the use of sulfhydrylgroup-containing amides or disulfide group-containing bis-amides fortreating or preventing abnormal skin conditions or diseases, and/orimproving the texture or appearance of the skin. Moreover, none of theabove references suggest the use of a compound which possesses thebenefits of α-hydroxy or salicylic acids while avoiding theirundesirable side effects. Thus, there is a need for cosmetic andpharmaceutical compositions with skin moisturizing and/or healingproperties of α-hydroxycarboxylic and salicylic but without theirdeleterious effects.

German Patent Publication DE 1643487 discloses methods of synthesisuseful for preparing various salts of S-substituted cysteamines.

PCT Publication No. WO 94/05302 to McCallum discloses the use ofcompositions comprising salicylic acid, elemental sulfur and cysteamineto treat "housewife dermatitis."

However, when compositions comprising more than one agent useful fortreating skin are intended to be formulated, solvents or vehicles whichsuccessfully dissolve or suspend one of the necessary agents may becompletely ineffective in dissolving or suspending the other(s), andvice versa. This can result in an excessive amount of time, energy andmanpower required for determining the proper formulation solvents orvehicles. Further, chemical interactions among the one or more agents ina single formulation may render each agent inactive, or simplyantagonize their activity. Thus, there remains a need for such acomposition which can be efficiently formulated and/or which utilizesthe advantages of one or more agents useful for treating skin.

As described below, the present invention provides novel compoundsuseful for treating or preventing abnormal skin conditions or diseases,and/or improving the texture or appearance of the skin with enhancedskin-healing properties. It further provides compounds which have theadvantages of α-hydroxycarboxylic and salicylic acids without theabove-mentioned biological disadvantages or formulation problems.

Additionally, the invention provides compositions comprising compoundshaving the advantages of α-hydroxycarboxylic and salicylic acids withoutthe above-mentioned drawbacks.

3. SUMMARY OF THE INVENTION

The present invention provides novel sulfhydryl group-containing amidesand disulfide group-containing bis(amides) useful in treating orpreventing abnormal skin conditions or diseases and/or improving thetexture or appearance of the skin. Also encompassed are compositionscomprising the sulfhydryl group-containing amides, the disulfidegroup-containing bis(amides) or mixtures thereof, said compositionsbeing particularly suited for topical application. Finally, theinvention includes methods for treating or preventing an abnormalbiological skin condition, and improving the texture or appearance ofthe skin using the compositions described herein.

In particular, the invention encompasses sulfhydryl group-containingamides, useful for treating or preventing abnormal skin conditions ordiseases and/or improving the texture or appearance of the skin, havingthe structure of formula I:

    R--NH--Z--SH                                               (I)

and pharmaceutically or cosmetically acceptable salts thereof, wherein:

R is selected from the group consisting of (A)(A)C(OH)--C(O)-- and2--(HO)C₆ H₄ C(O)--; wherein each A is independently selected from thegroup consisting of hydrogen, phenyl and a C₁ -C₂₂ alkyl or alkenylgroup, said C₁ -C₂₂ alkyl or alkenyl group being optionally substitutedwith one or more C₁ -C₄ alkyl groups, phenyl, halogen or hydroxylgroups, said phenyl being optionally substituted with one or more C₁ -C₄alkyl, halogen, hydroxyl groups or methoxyl groups; and

Z is selected from the group consisting of C₂ -C₁₂ alkyl, C₂ -C₁₂alkenyl and C₂ -C₁₂ alkynyl.

In a preferred embodiment of the invention, R is selected from the groupconsisting of 2-hydroxyethanoyl, 2-hydroxypropanoyl,2-methyl-2-hydroxypropanoyl, 2-hydroxybutanoyl, 2-hydroxypentanoyl,2-hydroxynonanoyl, 2-hydroxydecanoyl, 2-hydroxyoctanoyl,2-hydroxydodecanoyl, 2-hydroxytetradecanoyl, 2-hydroxyhexadecanoyl,2-hydroxyoctadecanoyl, 2-hydroxyeicosanoyl,2-hydroxyphenyl-2-hydroxyethanoyl, 2,2-diphenyl-2-hydroxyethanol,3-phenyl-2-hydroxypropanoyl, 2-phenyl-2-methyl-2-hydroxyethanoyl,2-(4'-chlorophenyl)-2-hydroxyethanoyl,2-(4'-hydroxy-3'methoxyphenyl)-2-hydroxyethanoyl,3-(2'-hydroxyphenyl)-2-hydroxypropanoyl,3-(4'-hydroxyphenyl)-2-hydroxypropanoyl,2-(3',4'-dihydroxyphenyl)-2-hydroxyethanoyl, and salicylyl,

wherein A is defined above; and Z is C₂ -C₆ alkyl, most preferably C₂alkyl.

Most preferred compounds of formula I are:

N-(salicylyl)cysteamine;

N-(lactyl)cysteamine;

N-(2-hydroxyoctanoyl)cysteamine;

N-(2-hydroxydecanoyl)cysteamine; and

N-(2-hydroxydodecanoyl)cysteamine.

It is to be understood that the compounds of formula I are alternativelyrepresented by the structure of formula II:

    (A)(A)C(OH)--C(O)--NH--Z--SH                               (II)

wherein A and Z are defined above; and by the structure of formula III:

    2-(HO)C.sub.6 H.sub.4 C(O)--NH--Z--SH                      (III)

wherein Z is defined above.

In a further aspect of the invention, the invention encompassesdisulfide group-containing bis-amides, useful in treating or preventingabnormal skin conditions or diseases and/or improving the texture orappearance of the skin, having the structure of formula IV:

    R--NH--Z--S--S--Z--NH--R                                   (IV)

and pharmaceutically or cosmetically acceptable salts thereof, wherein:

each R is independently selected from the group consisting of(A)(A)C(OH)--C(O)-- and 2-(HO)C₆ H₄ C(O)--, wherein each A isindependently selected from the group consisting of hydrogen, phenyl anda C₁ -C₂₂ alkyl or alkenyl group, said C₁ -C₂₂ alkyl or alkenyl groupbeing optionally substituted with one or more C₁ -C₄ alkyl groups,phenyl, halogen or hydroxyl groups, said phenyl being optionallysubstituted with one or more C₁ -C₄ alkyl, halogen, hydroxyl groups ormethoxyl group; and

each Z is independently selected from the group consisting of C₂ -C₁₂alkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl.

In a preferred embodiment of the invention, each R is independentlyselected from the group consisting of 2-hydroxyethanoyl,2-hydroxypropanoyl, 2-methyl-2-hydroxypropanoyl, 2-hydroxybutanoyl,2-hydroxypentanoyl, 2-hydroxynonanoyl, 2-hydroxydecanoyl,2-hydroxyoctanoyl, 2-hydroxydodecanoyl, 2-hydroxytetradecanoyl,2-hydroxyhexadecanoyl, 2-hydroxyoctadecanoyl, 2-hydroxyeicosanoyl,2-hydroxyphenyl-2-hydroxyethanoyl, 2,2-diphenyl-2-hydroxyethanoyl,3-phenyl-2-hydroxypropanoyl, 2-phenyl-2-methyl-2-hydroxyethanoyl,2-(4'-chlorophenyl)-2-hydroxyethanoyl,2-(4'-hydroxy-3'methoxyphenyl)-2-hydroxyethanoyl,3-(2'-hydroxyphenyl)-2-hydroxypropanoyl,3-(4'-hydroxyphenyl)-2-hydroxypropanoyl, 2-(3',4'-dihydroxyphenyl)-2-hydroxyethanoyl, and salicylyl; and each Z ispreferably C₂ -C₆ alkyl, most preferably C₂ alkyl.

Most preferred compounds of formula IV are:

N,N'-Bis(salicylyl)cystamine;

N,N'-Bis(lactyl)cystamine;

N,N'-Bis(2-hydroxyoctanoyl)cystamine;

N,N'-Bis(2-hydroxydecanoyl)cystamine; and.

N,N'-Bis(2-hydroxydodecanoyl)cystamine.

It is to be understood that the compounds of formula IV arealternatively represented by the structures of formula V:

    (A)(A)C(OH)--C(O)--NH--Z--S--S--Z--NH--C(O)--(HO)C(A)(A)   (V)

wherein A and Z are defined above; and by the structure of formula VI:

    2-(HO)C.sub.6 H.sub.4 C(O)--NH--Z--S--S--Z--NH--(O)CC.sub.6 H.sub.4 -2-(OH)(VI)

wherein Z is defined above.

In further embodiments, the invention encompasses cosmetic andpharmaceutical compositions containing one or more compounds of formulaI or formula IV, or a pharmaceutically or cosmetically acceptable saltthereof, and a pharmaceutically or cosmetically acceptable carrier orexcipient.

It is to be pointed out that the pharmaceutical compositions of thepresent invention are those which, when administered to the skin, rendera benefit or an effect of treating or preventing an abnormal biologicalcondition or a disease. Benefits or effects of treating or preventingsuch abnormal condition or disease are the reduction in severity ordisappearance of the abnormal condition or disease. The reduction inseverity or disappearance of the abnormal condition or disease may beeither in the short- or long-term. Such abnormal biological conditionsor diseases to be treated by administering a composition of the presentinvention include, but are not limited to dry skin, severe dry skin,dandruff, acne, keratoses, psoriasis, eczema, skin flakiness, pruritus,age spots, lentigines, melasmas, wrinkles (both coarse and fine, causedby intrinsic as well as extrinsic damage), warts, blemished skin,hyperpigmented skin, hyperkeratotic skin, inflammatory dermatoses,age-related skin changes and skin in need of cleansers, as well as theeffects of skin atrophy.

It is to be further pointed out that the cosmetic compositions of thepresent invention are those which, when administered to the skin,improve the texture or appearance thereof, without necessarily renderinga benefit or an effect of treating or preventing an abnormal biologicalcondition or a disease. In this context, improving the texture orappearance of the skin is meant to encompass enhancing the skin'snatural look and/or feel so as to increase the beauty and/or smoothnessof the skin from its pre-treated state, or to mask unwanted symptoms ofan abnormal biological condition or a disease. This can includeproviding a temporary moisturizing effect to the epidermis of the skin.Such abnormal biological conditions or diseases include, but are notlimited to dry skin, severe dry skin, dandruff, acne, keratoses,psoriasis, eczema, skin flakiness, pruritus, age spots, lentigines,melasmas, wrinkles (both coarse and fine, caused by intrinsic as well asextrinsic damage), warts, blemished skin, hyperpigmented skin,hyperkeratotic skin, inflammatory dermatoses, age-related skin changesand skin in need of cleansers, as well as the effects of skin atrophy.

In a still further embodiment, the invention encompasses methods forregulating skin atrophy comprising administering to a subject a safe andeffective amount of one or more compounds of formula I or formula IV, ora pharmaceutically or cosmetically acceptable salt thereof, as describedherein.

In yet another embodiment, the invention encompasses methods forregulating skin atrophy comprising administering to a subject a safe andeffective amount of a composition comprising one or more compounds offormula I or formula IV, or a pharmaceutically or cosmeticallyacceptable salt thereof and a pharmaceutically or cosmeticallyacceptable carrier or excipient.

In yet another embodiment, the invention encompasses methods fortreating disorders including but not limited to dry skin, severe dryskin, dandruff, acne, keratoses, psoriasis, eczema, skin flakiness,pruritus, age spots, lentigines, melasmas, wrinkles (both coarse andfine, caused by intrinsic as well as extrinsic damage), warts, blemishedskin, hyperpigmented skin, hyperkeratotic skin, inflammatory dermatoses,age-related skin changes and skin in need of cleansers.

The compounds of the present invention surprisingly demonstratepharmaceutical activity or cosmetic effects against skin disordersheretofore not achieved by α-hydroxycarboxylic or salicylic acidsthemselves or by the combination of α-hydroxycarboxylic or salicylicacids with sulfur-containing compounds such as cysteamine and cystamine.

The present invention may be understood more fully by reference to thedetailed description and illustrative examples which are intended toexemplify non-limiting embodiments of the invention.

4. DETAILED DESCRIPTION OF THE INVENTION 4.1. Definitions

As used herein, "skin atrophy" means the thinning and/or generaldegradation of the dermis layer of mammalian skin often characterized bya decrease in collagen and/or elastin as well as decreased number, sizeand doubling potential of fibroblast cells. Skin atrophy is a naturalresult of aging. Skin atrophy may be caused by either intrinsic orextrinsic factors such as natural chronoaging, photodamage, burns orchemical damage, or by exposure to pollutants or allergens, e.g.,cigarette smoke. Skin atrophy is often an undesirable side effectresulting from treatment with α-hydroxycarboxylic or salicylic acids.

As used herein, "regulating skin atrophy" means preventing, retarding,arresting, treating or reversing the process of atrophy in mammalianskin.

As used herein, "safe and effective amount" means an amount of compoundor composition sufficient to significantly induce a positivemodification in the condition to be treated, but low enough to avoidserious side effects (at a reasonable benefit/risk ratio), within thescope of sound medical judgment. The safe and effective amount of thecompound or composition will vary with the particular condition beingtreated, the age and physical condition of the patient being treated,the severity of the condition, the duration of the treatment, the natureof concurrent therapy, the specific compound, compounds or compositionemployed, the particular pharmaceutically-acceptable carrier utilized,and like factors within the knowledge and expertise of the attendingphysician or health care provider.

As used herein, "amide" means any compound of formula I wherein theamino group of a thioamine is covalently bonded to the carbonyl group ofan α-hydroxycarboxylic acid or salicylic acid moiety, forming an amidebond therewith.

As used herein, "bis-amide" means any compound of formula IV wherein theamino groups of a diaminodisulfide are covalently bonded to the carbonylgroup of an α-hydroxycarboxylic acid or salicylic acid moiety, formingamide bonds therewith.

As used herein, "cosmetic" means a formulation to be administered to theskin which improves the texture or appearance thereof, withoutnecessarily rendering a benefit or an effect of treating or preventingan abnormal biological condition or a disease. Such improvement includesproviding a temporary moisturizing effect to the epidermis of mammalianskin. A safe and effective amount of a cosmetic means an amount of thecosmetic sufficient to render a beneficial effect to the skin, but lowenough to avoid side effects, such as, damaging the structure orfunction of the skin.

As used herein, "pharmaceutical" means a formulation to be administeredto the skin which renders a benefit or an effect of treating orpreventing an abnormal biological condition or a disease.

As used herein, "alkyl" means a saturated hydrocarbon. Further, the term"alkyl" as used herein includes both straight, e.g., n-propyl, n-butyl,n-pently, etc., and branched, e.g., isopropyl, t-butyl, isopentyl, etc.,chained hydrocarbons.

As used herein, "alkenyl" means a hydrocarbon having at least one doublebond.

As used herein, "alkynyl" means a hydrocarbon having at least one triplebond.

As used herein, "salicylyl" means 2-hydroxybenzoyl.

As used herein, "salicylate" means 2-hydroxybenzoate.

As used herein, "lactyl" means either d-, l- or dl-2-hydroxypropanoyl.

As used herein, "lactate" means either d-, l- or dl-2-hydroxypropanoate.

As used herein, "eq." means a molar equivalent relative to the limitingreagent in the reaction mixture.

4.2. Synthesis

The compounds of the present invention can be synthesized in accordancewith standard organic chemical techniques using readily/commerciallyavailable starting materials.

Examples of the synthesis of the compounds of formula I and formula IVare described below in Scheme 1. ##STR1##

Thioamine 1, where Z is defined above, can be prepared from HO--Z--NH₂and carbon disulfide, followed by hydrolysis of the cyclic intermediate(Mills Jr. et al., J. Am. Chem. Soc., 62:1173 (1940)), whereinHO--Z--NH₂ is prepared from an ω-hydroxycarboxylic acid of the formulaHO--Y--COOH, where Y is C₃ -C₁₂ alkyl, C₃ -C₁₂ alkenyl and C₃ -C₁₂alkynyl, by protection of the ω-hydroxyl group (T. D. Greene, ProtectingGroups in Organic Synthesis, John Wiley & Sons, New York, 1981) followedby amidation with ammonia or its equivalent, reduction of the amidecarbonyl with lithium aluminum hydride or any other reducing agent knownby those of ordinary skill in the art useful for reducing lactamcarbonyl groups and removal of the protecting group. Alternatively, whenZ═CH₂ CH₂, thioamine 1 can be prepared via reaction betweenethyleneimine and hydrogen sulfide (Mills Jr. et al., J. Am. Chem. Soc.,62:1173 (1940)) or obtained commercially as its hydrochloride salt from,for example, Aldrich Chemical Company, Inc., Milwaukee, Wis. Suchhydrochloride or other acid salts of thioamine 1 can be converted totheir free base form by dissolving the acid salt of 1 in a suitableorganic solvent such as, for example, methylene chloride, and washingthe organic solution of the acid salt of 1 with a base, preferably withan aqueous solution of a base such as an alkali metal or alkaline earthbicarbonate, carbonate or hydroxide, until the washings are of basic pH.The organic solution containing the free base form of thioamine 1 canoptionally be dried and then concentrated to afford the free base formof thioamine 1.

Thioamime 1 is then amidated with either an α-hydroxycarboxylic acid ofthe formula (A)(A)C(OH)--CO₂ H or a hydroxybenzoic acid of the formula2-(HO)C₆ H₄ CO₂ H, wherein A is defined above. Optionally, thioamine 1is amidated with a protected α-hydroxycarboxylic acid having the formula(A)(A)C(OP)--CO₂ H or a protected hydroxybenzoic acid of the formula2-(PO)C₆ H₄ CO₂ H, wherein A is defined as above and P is a suitableprotecting group which allows the thioamine amino group to participatein an amidation reaction with the carboxyl group of either protected orunprotected carboxylic acid without interference from the unprotectedhydroxyl group. It is to be understood that the (HO) moiety of 2-(HO)C₆H₄ CO₂ H or the (PO) moiety of 2-(PO)C₆ H₄ CO₂ H is "ortho" relative tothe carboxyl group. Suitable protecting groups are those which may beremoved subsequent to the amidation reaction with thioamine 1 withoutresulting in cleavage of the newly formed amide bond. Examples of suchprotecting groups may be found in T. D. Greene, Protecting Groups inOrganic Synthesis, John Wiley & Sons, New York, 1981. Where A isoptionally substituted with one or more hydroxyl groups, one or :more ofthose hydroxyl groups may be optionally protected with a suitableprotecting group found in T. D. Greene, Protecting Groups in OrganicSynthesis, John Wiley & Sons, New York, 1981.

Thioamine 1 can be heated with either the protected or unprotectedcarboxylic acids, optionally in the presence of an acid catalyst, toobtain amides 2 or 3, respectively. Such an amidation proceeds withconcomitant loss of water. The amidation reaction can proceed in asuitable, preferably high boiling, organic solvent, or can proceed neatin the absence of solvent. Suitable acid catalysts which can be usedinclude, but are not limited to hydrochloric acid, sulfuric acid,p-toluene sulfonic acid, methanesulfonic acid and other such acidcatalysts known to those skilled in the art. Where the hydroxyl group ofeither (A)(A)C(OH)--CO₂ H or 2-(HO)C₆ H₄ CO₂ H is protected with aprotecting group, the protecting group (P) should be stable to acidicconditions.

The amidation of thioamine 1 with either (A)(A)C(OH)--CO₂ H,(A)(A)C(OP)--CO₂ H, 2-(HO)C₆ H₄ CO₂ H or 2-(PO)C₆ H₄ CO₂ H, or analkylester derivative thereof, is preferably conducted in the presenceof a reaction solvent including, but not limited to methylene chloride,chloroform, carbon tetrachloride, benzene, toluene, xylenes,tetrahydrofuran, diethyl ether, other suitable solvents known to thoseskilled in the art, and mixtures thereof.

Preferably, the protected or unprotected carboxylic acids are convertedto their respective alkyl ester derivatives, preferably methyl esterderivatives, prior to amidation with thioamine 1 via means recitedabove. The alkyl esters are prepared by treating the carboxylic acids,optionally in the presence of organic solvent, with the desired alkanol,preferably methanol, followed by thionyl chloride. After esterificationis complete, the resulting mixture is neutralized via the addition ofbase, preferably an alkali metal or alkaline earth carbonate orbicarbonate. The resulting mixture is purified via conventional means,i.e., distillation, column chromatography, recrystallization and thelike, to afford the desired alkyl ester derivative. The alkyl esters canalso be prepared by heating the protected or unprotected carboxylicacids in a desired alkanol, preferably methanol, in the presence of anacid catalyst recited above but in the absence of thionyl chloride.Purification via standard means such as distillation, columnchromatography, or recrystallization affords the desired alkyl esterderivative.

The protected or unprotected carboxylic acids may also be converted totheir acid halide derivatives, preferably acid chloride derivatives,prior to amidation with 1. The protected or unprotected carboxylic acidsmay be treated with either thionyl chloride or oxalyl chloride to givethe corresponding acid chlorides, which may then react with 1 to giveamides 2 and 3 respectively. Such an amidation is generally performed inan organic solvent including, but not limited to methylene chloride,chloroform, carbon tetrachloride, benzene, toluene, xylenes,tetrahydrofuran, diethyl ether, other aprotic organic solvents known tothose skilled in the art, and mixtures thereof. The amidation ofthioamine 1 with an acid chloride derivative of the carboxylic acids(A)(A)C(OH)--CO₂ H, (A)(A)C(OP)--CO₂ H, 2-(HO)C₆ H₄ CO₂ H or 2-(PO)C₆ H₄CO₂ H is preferably performed in the presence of a base including, butnot limited to triethylamine, diisopropylethylamine, pyridine,4-dimethylaminopyridine, other bases known to those skilled in the art,and mixtures thereof. If 1 and the protected or unprotected carboxylicacids are soluble in the base, the organic solvent may optionally beomitted.

In addition, thioamine 1 may be amidated by either the protected orunprotected carboxylic acids in the presence of coupling agents such asdicyclohexylcarbodiimide. When dicyclohexylcarbodiimide is used, it maybe advantageous to protect the sulfhydryl group of thioamine 1 with aprotecting group described in T. W. Greene, Protective Groups in OrganicSynthesis, John Wiley & Sons, New York, 1981. Preferably, a protectedcarboxylic acid having the formula (A)(A)C(OP)--CO₂ H or 2-(PO)C₆ H₄ CO₂H is used. Such a reaction is generally performed in an organic solventas described above.

If either (A)(A)C(OP)--CO₂ H or 2-(PO)C₆ H₄ CO₂ H is used to amidate 1,the protecting group (P) is removed to give amides 2 or 3, respectively.Methods for removing the protecting group can be found in T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,1981.

Diaminodisulfide 4, a starting material for bis-amides 5 and 6, can beprepared via hydrogen peroxide oxidation of 1 (Mills Jr. et al., J. Am.Chem. Soc., 62:1173 (1940)). Moreover, diaminodisulfide 4 can beconverted back to 1 via reduction with NaBH₄ /AlCl₃. For example,diaminodisulfide 4 is dissolved in a polar organic solvent, preferablydiethylene glycol monomethyl ether, and treated with 5-20 eq.,preferably 10-15 eq. of NaBH₄ and 1-5 eq., preferably 1-2 eq. of AlCl₃.After the reaction is complete, the reaction mixture is quenched withaqueous acid and the sulfhydryl group-containing amide product isextracted into organic solvent. The organic solvent containing the amideproduct is optionally dried using conventional drying agents includingthose described above and purified by distillation, columnchromatography, recrystallization or other means known to those skilledin the art to afford thioamine 1. In this way, either 1 or 4 can serveas a starting material for amides 2 and 3 or bis-amides 5 and 6.

Diaminodisulfide 4, when Z═CH₂ CH₂, can be obtained commercially as itshydrochloride salt from, for example, Aldrich Chemical Company, Inc.,Milwaukee, Wis. Such hydrochloride or other acid salts ofdiaminodisulfide 4, such is for example the hydrosulfate salt of 4, canbe converted to their free base form by dissolving the acid salt of 4 ina suitable organic solvent such as, for example, methylene chloride, andwashing the organic solution of the acid salt of 4 with a base,preferably an alkali metal or alkaline earth bicarbonate, carbonate orhydroxide in aqueous solution, until the washings are of basic pH. Theorganic solution containing the free base form of diaminodisulfide 4 canbe optionally dried using drying agents such as sodium sulfate,potassium carbonate and preferably magnesium sulfate, and thenconcentrated to afford the free base form of 4.

Diaminodisulfide 4 is then bis-amidated with either anα-hydroxycarboxylic acid of the formula (A)(A)C(OH)--CO₂ H or ahydroxybenzoic acid of the formula 2-(HO)C₆ H₄ CO₂ H, wherein A isdefined above. Optionally, diaminodisulfide 4 is bis-amidated with aprotected α-hydroxycarboxylic acid having the formula (A)(A)C(OP)--CO₂ Hor a protected hydroxybenzoic acid of the formula 2-(PO)C₆ H₄ CO₂ H,wherein A is defined as above and P is a suitable protecting group whichallows the thioamine amino group to participate in an amidation reactionwith the carboxyl group of either protected or unprotected carboxylicacid without interference from the unprotected hydroxyl group. It is tobe understood that the (HO) moiety of 2-(HO)C₆ H₄ CO₂ H or the (PO)moiety of 2-(PO)C₆ H₄ CO₂ H is "ortho" relative to the carboxyl group.Suitable protecting groups are those which may be removed subsequent tothe bis-amidation reaction with diaminodisulfide 4 without resulting incleavage of the newly formed amide bonds. Examples of such protectinggroups may be found in T. D. Greene, Protecting Groups in OrganicSynthesis, John Wiley & Sons, New York, 1981. Where A is optionallysubstituted with one or more hydroxyl groups, one or more of thosehydroxyl groups may be optionally protected with a suitable protectinggroup as defined in T. D. Greene, Protecting Groups in OrganicSynthesis, John Wiley & Sons, New York, 1981.

Diaminodisulfide 4 can be heated with either the protected orunprotected carboxylic acids, optionally in the presence of an acidcatalyst, to obtain bis-amides 5 or 6, respectively. Such bis-amidationproceeds with concomitant loss of water. The bis-amidation reaction canproceed in a suitable, preferably high boiling, organic solvent, or canproceed neat in the absence of solvent. Suitable acid catalysts whichcan be used include, but are not limited to hydrochloric acid, sulfuricacid, p-toluene sulfonic acid, methanesulfonic acid and other such acidcatalysts known to those skilled in the art. Where the hydroxyl group ofeither (A)(A)C(OH)--CO₂ H or 2-(HO)C₆ H₄ CO₂ H is protected with aprotecting group, the protecting group (P) should be stable to acidicconditions. The bis-amidation of diaminodisulfide 4 with either(A)(A)C(OH)--CO₂ H, (A)(A)C(OP)--CO₂ H, 2-(HO)C₆ H₄ CO₂ H or 2-(PO)C₆ H₄CO₂ H, or an alkylester derivative thereof, is preferably conducted inthe presence of a reaction solvent including, but not limited tomethylene chloride, chloroform, carbon tetrachloride, benzene, toluene,xylenes, tetrahydrofuran, diethyl ether, other suitable solvents knownto those skilled in the art, and mixtures thereof.

Preferably, the protected or unprotected carboxylic acids are convertedto their respective alkyl ester derivatives, preferably methyl esterderivatives, prior to bis-amidation with diaminodisulfide 4 via meansrecited above. The alkyl esters are prepared by treating the carboxylicacids, optionally in the presence of organic solvent, with the desiredalkanol, preferably methanol, followed by thionyl chloride. Afteresterification is complete, the resulting mixture is neutralized via theaddition of base, preferably an alkali metal or alkaline earth carbonateor bicarbonate. The resulting mixture is purified via conventionalmeans, i.e., distillation, column chromatography, recrystallization orthe like, to afford the desired alkyl ester derivative. The alkyl esterscan also be prepared by heating the protected or unprotected carboxylicacids in a desired alkanol, preferably methanol, in the presence of anacid catalyst recited above but in the absence of thionyl chloride.Purification via standard means such as distillation, columnchromatography, or recrystallization affords the desired alkyl esterderivative.

The protected or unprotected carboxylic acids may also be converted totheir acid halide derivatives, preferably acid chloride derivatives,prior to bis-amidation with 4. The protected or unprotected carboxylicacids may be treated with either thionyl chloride or oxalyl chloride togive the corresponding acid chlorides, which may then react with 4 togive bis-amides 5 and 6 respectively. Such bis-amidation is generallyperformed in an organic solvent including, but not limited to methylenechloride, chloroform, carbon tetrachloride, benzene, toluene, xylenes,tetrahydrofuran, diethyl ether, other aprotic organic solvents known tothose skilled in the art, and mixtures thereof. The bis-amidation ofdiaminodisulfide 4 with an acid chloride derivative of the carboxylicacids (A)(A)C(OH)--CO₂ H, (A)(A)C(OP)--CO₂ H, 2-(HO)C₆ H₄ CO₂ H or2-(PO)C₆ H₄ CO₂ H is preferably performed in the presence of a baseincluding, but not limited to triethylamine, diisopropylethylamine,pyridine, 4-dimethylaminopyridine, other bases known to those skilled inthe art, and mixtures thereof. If 4 and the protected or unprotectedcarboxylic acids are soluble in the base, the organic solvent mayoptionally be omitted.

In addition, diaminodisulfide 4 may be bis-amidated by either theprotected or unprotected carboxylic acids in the presence ofdicyclohexylcarbodiimide. When dicyclohexylcarbodiimide is used it maybe advantageous to protect the sulfhydryl groups of diaminodisulfide 4with a protecting group described in T. W. Greene, Protective Groups inOrganic Synthesis, John Wiley & Sons, New York, 1981. Preferably, aprotected carboxylic acid is used. Such a reaction is generallyperformed in an organic solvent as described above.

If either (A)(A)C(OP)--CO₂ H or 2-(PO)C₆ H₄ CO₂ H is used to bis-amidate4, the protecting group (P) is removed to give bis-amides 5 or 6,respectively. Methods for removing the protecting group can be found inT. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons,New York, 1981.

In a further embodiment of the invention, bis-amides 5 and 6 can beprepared in a step-wise fashion such that the α-hydroxycarboxylic orsalicylic acid moiety on each terminus of bis-amides 5 or 6 isdifferent. For example, a thioamine 1 can be oxidatively coupled, usinghydrogen peroxide (Mills Jr. et al., J. Am. Chem. Soc., 62:1173 (1940))to a second thioamine which is N-protected with a protecting groupstable to hydrogen peroxide. It is well within the purview of one ofordinary skill in the art to select such a protecting group.

The resulting diaminodisulfide 4 bears an N-protected amino group at oneterminus of the molecule and an unprotected amino group at the otherterminus. The resulting mono-protected diaminodisulfide is then amidatedwith an optionally protected first α-hydroxy or salicylic acid orderivative thereof using any of the methods described above. Theprotecting group is then removed from the amide adduct using conditionswhich will not hydrolyze or otherwise cleave the newly-formed amidebond, thereby exposing a free amino group available for a secondamidation. The free amino group is then amidated with an optionallyprotected second α-hydroxy or salicylic acid or derivative thereof,which is the same or different from the optionally protected firstα-hydroxy or salicylic acid or derivative thereof, using any of themethods described above. By this method, unsymmetrical bis-amidesderived ultimately from thioamine 1, having different α-hydroxy orsalicylic acid groups on each terminus, can be obtained.

Furthermore, bis-amides 5 and 6 can be directly converted to amides 2and 3, respectively, via treatment with NaBH₄ /AlCl₃. The desiredbis-amide is dissolved in a polar organic solvent, preferably diethyleneglycol monomethyl ether, and treated with 5-20 eq., preferably 10-15 eq.of NaBH₄ and 1-5 eq., preferably 1-2 eq. of AlCl₃. After the reaction iscomplete, the reaction mixture is quenched with aqueous acid and theamide product is extracted into organic solvent. The organic solventcontaining the amide product is optionally dried using conventionaldrying agents including those described above and purified bydistillation, column chromatography, recrystallization or other meansknown to those skilled in the art to afford amides 2 or 3.

If a heterogeneous mixture of amides is desired, an unsymmetricalbis-amide is first prepared from diaminodisulfide 4, as described above.The resulting unsymmetrical bis-amide is then treated with NaBH₄ /AlCl₃,as described above, so as to cleave the disulfide bond thereof andafford a 1:1 mixture of different thioamides.

It is to be understood that in addition to using the synthetic methodsdescribed hereinabove to obtain starting materials for the amides andbis-amides of the present invention, starting materials such as alkylesters of α-hydroxycarboxylic acids and salicylic acid can be obtainedcommercially. For example, methyl salicylate and the d- and l-enantiomers of methyl lactate can be obtained from Aldrich Chemical Co.,Milwaukee, Wis.

4.3. Compositions

The compositions of the present invention can be used to treat skinatrophy and other disorders including but not limited to dry skin,severe dry skin, dandruff, acne, keratoses, psoriasis, eczema, skinflakiness, pruritus, age spots, lentigines, melasmas, wrinkles (bothcoarse and fine, caused by intrinsic as well as extrinsic damage),warts, blemished skin, hyperpigmented skin, hyperkeratotic skin,inflammatory dermatoses, age-related skin changes and skin in need ofcleansers.

In treating or preventing an abnormal biological condition or a diseasesuch as skin atrophy or any other skin disorder described above,pharmaceutical compositions containing about 0.005 to about 50 wt. %,preferably 0.01 to about 25 wt. % and most preferably 0.01 to about 5wt. % of the amide of formula I or bis-amide of formula IV can beemployed.

In improving the texture or appearance of the skin, topical cosmeticcompositions containing 0.005 to about 50 wt. %, preferably 0.005 toabout 1 wt. % and most preferably 0.005 to about 0.5 wt. % of the amideof formula I or bis-amide of formula IV can be employed.

It should be understood that two or more amides or bis-amides amides ofthe present invention can be used in combination such that the combinedweight % of those amides or bis-amides used in the above-mentionedcompositions is within those ranges mentioned above. Such compositionsare preferably to be administered topically, so as to minimize systemiceffects or undesirable side effects.

The novel compounds may also be employed in pharmaceutical compositionssuitable for parenteral (including subcutaneous, transdermal,intramuscular and intravenous) administration, although the mostsuitable route in any case will depend on the nature and severity of thecondition being treated. The most preferred mode of administration fortreating skin disorders, in particular skin atrophy or the skindisorders described above, is topical.

In addition, the amides and bis-amides of the present invention may befurther employed in cosmetic compositions. In such an instance, thepreferred mode of administration for improving the texture or appearanceof the skin is topical.

The amides and bis-amides of the present invention can be formulatedinto suitable cosmetic or pharmaceutical compositions depending on theparticular use for which it is to be intended, for example, cosmetic ortherapeutic. The pharmaceutical and cosmetic compositions can compriseone or more of the amides of formula I or bis-amides of formula IV and apharmaceutically or cosmetically acceptable carrier or excipient.Examples of such pharmaceutically acceptable carriers or excipients arewell known to those skilled in the art and can be found, for example, inRemington's Pharmaceutical Sciences, Eighteenth Edition, A. R. Gennaro,Ed., Mack Publishing Co., Easton, Pa., 1990. Examples of suchcosmetically acceptable carriers or excipients are well known to thoseskilled in the art and can also be found, for example, in CTFAInternational Cosmetic Ingredient Dictionary, Fourth Edition, J. M.Nikitakis, Ed., The Cosmetic, Toiletry, and Fragrance Association,Washington, D.C., 1991.

The pharmaceutical and cosmetic compositions of the present inventionintended for topical application may contain carrier, excipient orvehicle ingredients such as, for example, water, acetone, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof to form lotions,tinctures, creams, emulsions, mousses, sprays, foams, powders, gels orointments which are non-toxic and pharmaceutically or dermatologicallyacceptable. Additionally, moisturizers or humectants can be added to thepresent compositions if desired. Examples of such additional ingredientsuseful for pharmaceutical compositions can be found in Remington'sPharmaceutical Sciences, Eighteenth Edition, A. R. Gennaro, Ed., MackPublishing Co., Easton, Pa., 1990. Examples of such additionalingredients useful for cosmetic compositions can be found in CTFAInternational Cosmetic Ingredient Dictionary, Fourth Edition, J. M.Nikitakis, Ed., The Cosmetic, Toiletry, and Fragrance Association,Washington, D.C., 1991.

In addition to these and other vehicles which will be obvious to thoseof ordinary skill in the art, it will be understood that thepharmaceutical and cosmetic compositions of the present invention mayinclude other ingredients such as those that improve or eradicate agespots, keratoses and wrinkles; pigments; analgesics; anesthetics;antiacne agents; antibacterials; antiyeast agents; antifungal agents;antiviral agents; antidandruff agents; antidermatitis agents;antipruritic agents; antiemetics; antimotion sickness agents;antiinflammatory agents; antihyperkeratolytic agents; antidryskinagents; antiperspirants; antipsoriatic agents; antiseborrheic agents;hair conditioners and hair treatment agents; antiaging agents;antiwrinkle agents; antiasthmatic agents and bronchodilators; sunscreenagents; antihistamine agents; skin lightening agents; depigmentingagents; vitamins; corticosteroids; tanning agents; hormones; retinoids;topical cardiovascular agents; clotrimazole; ketoconazole; miconazole;griseofulvin; hydroxyzine; diphenhydramine; pramoxine; lidocaine;procaine; mepivacaine; monobenzone; erythidocaine; procaine;mepivacaine; monobenzone; erythromycin; tetracycline; clindamycin;meclocyline; hydroquinone; minocycline; naproxen; ibuprofen;theophylline; cromolyn; albuterol; retinoic acid; 13-cis retinoic acid;hydrocortisone; hydrocortisone 21-acetate; hydro-cortisone 17-valerate;hydrocortisone 17-butyrate; betamethasone valerate; betamethasonedipropionate; triamcinolone acetonide; fluocinonide; clobetasolpropionate; benzoyl peroxide; crotamiton; propranolol; promethazine;vitamin A palmitate; vitamin E acetate and mixtures thereof.Concentrations of these ingredients will vary depending upon intendeduse, i.e., therapeutic or cosmetic.

Moreover, it will be understood that the pharmaceutical and cosmeticcompositions of the present invention can additionally include one ormore hydroxyacids, which are well known to the skilled artisan asdescribed above, present in an effective amount to improve theappearance or the texture of the skin. The hydroxyacid(s) can be presentin an amount ranging from about 0.5 to about 15% by weight. A preferredcomposition is a cosmetic composition, in which the total amount ofhydroxyacid(s) is preferably from about 0.5 to about 5%, more preferablyfrom about 0.5 to about 3%, and most preferably from about 0.75% toabout 2%. For the purposes of the present invention, the term"hydroxyacid," "hydroxyacids" or "hydroxyacid(s)" includes both alpha-and beta-hydroxyacids in their free acid form, as well as covalentderivatives thereof. Suitable hydroxyacids include, but are not limitedto, alpha-hydroxyacids such as lactic acid, glycolic acid, citric acid,alpha-hydroxyoctanoic acid, alpha-hydroxydecanoic acid,alpha-hydroxylauric acid, tartaric acid, glucouronic acid, galactouronicacid, alpha-hydroxybutyric acid, alpha-hydroxyisobutyric acid, malicacid, mandelic acid, pyruvic acid, and tartronic acid, preferablyalpha-hydroxydecanoic and alpha-hydroxyoctanoic acids; and beta-hydroxyacids such as salicylic acid. Suitable covalent derivatives includeesters, thioesters, amides and lactones, and mixtures thereof. In apreferred embodiment, the composition comprises a mixture of freehydroxyacids, such as alpha-hydroxydecanoic, alpha-hydroxyoctanoic andsalicylic acids.

The amides and bis-amides of the present invention can be used as theirpharmaceutically or cosmetically acceptable salts. Such salts include,but are not limited to, hydrochloride, hydrobromide, hydroiodide,acetate, citrate, tartrate, malate, ammonium, alkylammonium salts andthe like, as well as salts of one or more alpha- or beta-hydroxyacidsdescribed above.

It is to be understood that the amides of formula I and bis-amides offormula IV can exist as a single, i.e., d- or l- enantiomer, or aracemic mixture thereof, as well as mixtures of diastereomers. Theinstant invention encompasses optical isomers of the compounds disclosedherein. Standard techniques for purification of enantiomers can be foundin, for example, Stereochemistry of Carbon Compounds by E. L. Eliel(McGraw Hill, 1962) and Tables of Resolving Agents by S. H. Wilen(University of Notre Dame Press, 1972).

4.4. Methods for Treating or Preventing an Abnormal Skin Condition orDisease

The present invention relates to a method for treating or preventing anabnormal skin condition or disease such as skin atrophy or other skindisorders including but not limited to dry skin, severe dry skin,dandruff, acne, keratoses, psoriasis, eczema, skin flakiness, pruritus,age spots, lentigines, melasmas, wrinkles (both coarse and fine, causedby intrinsic as well as extrinsic damage), warts, blemished skin,hyperpigmented skin, hyperkeratotic skin, inflammatory dermatoses,age-related skin changes and skin in need of cleansers. Such a methodcomprises administering to the skin a safe and effective amount of oneor more of the amides or bis-amides of the present invention. While thepresent invention relates to amides of formula I and bis-amides offormula IV used to treat skin disorders, the present invention furtherrelates to the use of compositions, such as those discussed above,comprising one or more of the amides or bis-amides of the presentinvention, to be used for treating skin disorders. The amount of amideor bis-amide and frequency of treatment will vary widely depending uponthe extent of skin disease or condition already in existence in thesubject (if such exists), the rate of progression of skin disease orcondition, and the extent of treatment desired.

A preferred method of treating the skin is via chronic topicalapplication of a safe and effective amount of the amide or bis-amide toregulate skin atrophy to treat or prevent the abnormal skin condition ordisease. The amount of amide or bis-amide and frequency of topicalapplication to the skin can vary widely, depending upon the particularskin disorder and the severity thereof. It is well within the purview ofthe skilled artisan, such as a dermatologist or other health careprovider, to regulate dosages according to patient needs. It issuggested as an example that topical application range from about onceper week to about 4 or 5 times daily, preferably from about 3 times aweek to about 3 times daily, most preferably about once or twice perday. The composition for topical application will comprise from about0.005% to about 50%, preferably from about 0.01% to about 25%, mostpreferably from about 0.01% to about 5% of the active compound ormixture of compounds. By "chronic" application, it is meant herein thatthe period of topical application may be over the lifetime of thepatient, preferably for a period of at least about one month, morepreferably from about three months to about twenty years, morepreferably from about six months to about ten years, more preferablystill from about one year to about five years, thereby resulting in thetreatment or prevention of the abnormal skin condition or diseasedescribed.

In another embodiment of the invention, treating or preventing anabnormal skin condition or disease involves administering both a safeand effective amount of the amide or bis-amide(s) and a safe andeffective amount of one or more of a sunscreening agent, ananti-inflammatory agent, an anti-oxidant/radical scavenging agent, achelating agent, a retinoid and/or a benzofuran derivative to the skinsimultaneously. As used herein, "simultaneous application" or"simultaneously" means administering the agents to the skin at the samesitus on the body at about the same time. Though this can beaccomplished by administering the agents separately to the skin,preferably a composition comprising all the desired agents commingled isadministered to the skin. The amount of sunscreening agent administeredis generally from about 0.02 mg to about 1.0 mg per cm² skin. The amountof anti-inflammatory agent administered is generally from about 0.005 mgto about 0.5 mg, preferably from about 0.01 mg to about 0.1 mg per cm²skin. The amount of chelating agent generally administered is from about0.001 mg to about 1.0 mg, preferably from about 0.01 mg to about 0.5 mg,more preferably from about 0.05 mg to about 0.1 mg per cm² skin. Theamount of retinoid administered is generally from about 0.00001 mg toabout 0.02 mg per cm² skin. The amount of benzofuran derivativeadministered is generally from about 0.001 mg to about 1.0 mg/cm² skinper application, preferably from about 0.01 to about 0.5 mg/cm² skin perapplication. The amount of amide or bis-amide(s) administered isgenerally from about 0.001 mg to about 1.0 mg per cm² skin perapplication, preferably from about 0.01 mg to about 0.5 mg per cm², morepreferably from about 0.05 to about 0.25 mg/cm² skin per application,which may vary upon the severity of the condition to be treated and theefficacy of the compounds employed.

4.5. Methods for Improving the Texture or Appearance of the Skin

The present invention also relates to a method for improving the textureor appearance of the skin. Improving the texture or appearance of theskin is meant to encompass enhancing the skin's natural look and/or feelso as to increase the beauty and/or smoothness of the skin from itspre-treated state, or to mask unwanted symptoms of an abnormalbiological condition or a disease. Such cosmetic uses include but arenot limited to moisturizing skin; masking skin blemishes or otherundesired attributes; highlighting the skin as, for example, an eyeshadow; improving skin texture; and the like. Such abnormal biologicalconditions or diseases include, but are not limited to dry skin, severedry skin, dandruff, acne, keratoses, psoriasis, eczema, skin flakiness,pruritus, age spots, lentigines, melasmas, wrinkles (both coarse andfine, caused by intrinsic as well as extrinsic damage), warts, blemishedskin, hyperpigmented skin, hyperkeratotic skin, inflammatory dermatoses,age-related skin changes and skin in need of cleansers, as well as theeffects of skin atrophy. Such a method comprises administering to theskin a safe and effective amount of one or more of the amides orbis-amides of the present invention. The amount of amide or bis-amideand frequency of topical application to the skin can vary widely,depending upon desirability of use by the skilled artisan, e.g., a userof cosmetics.

While the present invention relates to amides of formula I andbis-amides of formula IV used to treat skin disorders, the presentinvention further relates to the use of compositions, such as thosediscussed above, comprising one or more of the amides or bis-amides ofthe present invention, to be used for treating skin disorders.

A preferred method of treating the skin is via occasional topicalapplication of a safe and effective amount of the amide or bis-amide toimprove the texture or appearance of the skin. The amount of amide orbis-amide and frequency of treatment will vary widely depending upon thedesired level of improvement of the appearance or texture of the skinand/or the extent of an abnormal skin condition or disease, if one suchexists, desired to be masked. It is suggested as an example that topicalapplication range from about once per week to about 4 or 5 times daily,preferably from about 3 times a week to about 3 times daily, mostpreferably about once or twice per day. The composition for topicalapplication will comprise from about 0.005 to about 50 wt. %, preferably0.005 to about 1 wt. % and most preferably 0.005 to about 0.5 wt. % ofthe amide of formula I or bis-amide of formula IV. By "occasional"application, it is meant herein that the period of topical applicationmay be as often as desired and/or needed to improve the texture orappearance of the skin.

Cosmetic uses encompassed by the cosmetic compositions of the presentinvention include but are not limited to moisturizing skin; masking skinblemishes or other undesired attributes; highlighting the skin as, forexample, an eye shadow; improving skin texture; and the like. The amountof amide or bis-amide and frequency of topical application to the skincan vary widely, depending upon desirability of use.

In another embodiment of the invention, improving the texture orappearance of the skin involves administering both a safe and effectiveamount of the amide or bis-amide(s) and optionally, one or more of asunscreening agent, an anti-inflammatory agent, an anti-oxidant/radicalscavenging agent, a chelating agent, a retinoid and/or a benzofuranderivative to the skin simultaneously. As used herein, "simultaneousapplication" or "simultaneously" means administering the agents to theskin at the same situs on the body at about the same time. Though thiscan be accomplished by administering the agents separately to the skin,preferably a composition comprising all the desired agents commingled isadministered to the skin. If present, the amount of sunscreening agentadministered is generally from about 0.02 mg to about 1.0 mg per cm²skin; the amount of anti-inflammatory agent administered is generallyfrom about 0.005 mg to about 0.5 mg, preferably from about 0.01 mg toabout 0.1 mg per cm² skin; the amount of chelating agent generallyadministered is from about 0.001 mg to about 1.0 mg, preferably fromabout 0.01 mg to about 0.5 mg, more preferably from about 0.05 mg toabout 0.1 mg per cm² skin; the amount of retinoid administered isgenerally from about 0.00001 mg to about 0.02 mg per cm² skin; and theamount of benzofuran derivative administered is generally from about0.001 mg to about 1.0 mg/cm² skin per application, preferably from about0.01 to about 0.5 mg/cm² skin per application. The amount of amide orbis-amide(s) administered is generally from about 0.001 mg to about 1.0mg per cm² skin per application, preferably from about 0.001 mg to about0.1 mg per cm², more preferably from about 0.001 to about 0.05 mg/cm²skin per application.

The following specific, non-limiting examples concern the synthesis ofthe amides and bis-amides of the instant invention and the preparationof a topical lotion, topical cream, topical ointment and topical gelusing vehicles previously used in other preparations. The formulationsfor these preparations are given below in Table 3.

EXAMPLE 1

Methyl 2-Hydroxydecanoate. A 22 L 3-neck reaction flask equipped with acooling bath, an overhead stirrer, a thermocouple and a 1 L additionfunnel was charged with 4.70 kg of 2-hydroxydecanoic acid and 16 L ofmethanol. A drying tube was attached to the reaction flask and theaddition funnel was charged with 1 L of thionyl chloride. With efficientstirring, the contents of the reaction flask were chilled to between 0°and +5° C. and the addition of thionyl chloride was commenced. The rateof thionyl chloride addition was adjusted such that with continuedcooling, the temperature of the reaction flask remained between 0° and+5° C. Under these conditions, the 1 L of thionyl chloride, as well asan additional 1 L of thionyl chloride, was completed in <2 hours. It isimportant to note that if the temperature of the reaction flask isallowed to fall much below 0° C., the reaction mixture will solidify,causing the stirrer to seize. If this happens, the addition of thionylchloride must be halted, and the entire reaction mixture allowed to warmto room temperature to effect redissolution. With efficient stirring,the reaction mixture can once again be chilled to between 0° and +5° C.and the addition of thionyl chloride be completed.

Following the addition of thionyl chloride, the resulting reactionmixture was allowed to warm to room temperature overnight, withcontinuous stirring. The resulting solution was poured into a 100 Lpolypot equipped with a Lightening stirrer. Approximately 10 L of hexanewas then added. With vigorous stirring, solid NaHCO₃, in approximately500 g portions, was added until the vigorous evolution of gasessubsided. A 5% aqueous solution of NaHCO₃ was gradually added until theresulting vigorous evolution of gases subsided. The resulting mixturewas allowed to stir for an additional 15 minutes before siphoning offthe hexane layer. The residual aqueous layer was extracted a second timewith an additional 10 L portion of hexane. The hexane extracts werecombined, dried over Na₂ SO₄ and concentrated in vacuo to afford 5.05 kg(93%) of the title compound as a pale, yellow liquid, purity 98% bygas-liquid partition chromatography: IR exhibited ν(OH), ν(C═O) andν(C--O) bands consistent with the structure of the title compound.

EXAMPLE 2

N,N'-Bis(2-hydroxydecanoyl)cystamine. A 15 L polypot was charged with1.5 kg cystamine H₂ SO₄ and 2 L of methylene chloride. With vigorousstirring, an aqueous solution of 40% NaOH was added to the resultingsuspension and the resulting biphasic mixture was allowed to stir for anadditional 15 minutes. The organic layer was separated from the aqueouslayer with the aid of a siphon and the entire extraction process wasrepeated 2 additional times. Combined organic extracts were dried(MgSO₄) and concentrated in vacuo to yield 390 g (2.56 mole; 48% yield)of cystamine free-base.

The resulting cystamine free-base was treated with 4 L of toluene, andthe resulting mixture was transferred to a 12 L 3-neck flask equippedwith an overhead stirrer, heating mantle and reflux condenser. The 12 L3-neck flask containing the mixture of cystamine free-base and toluenewas charged with 1.60 kg of methyl 2-hydroxydecanoate obtained fromExample 1 and the resulting mixture was heated at reflux for 1 hour. Atthis point, the reflux condenser was turned from a vertical to a nearlyhorizontal position so as to allow distillation to occur. Over a 1-2hour period, approximately 1400 mL of distillant was collected. Thedistillant was biphasic and consisted mostly of toluene in the lowerlayer and methanol in the upper layer. The reflux condenser was returnedto its vertical reflux position and the reaction mixture was heatedunder a gentle reflux and with vigorous stirring for an additional 6hours during which time a heavy precipitate formed. Upon cooling to roomtemperature, the entire contents of the reaction vessel solidified. 5 Lof toluene were added and the resulting mixture was allowed to stiruntil a homogeneous suspension of solid material was obtained. Thesuspended solid was collected by vacuum filtration, washed with 4-5 L oftoluene, then with 4-5 L of ethyl acetate before being pressed dry.

The resulting crude product was dissolved in approximately 30 L of nearboiling γ-butyrolactone and the resulting solution was allowed to cooland stand overnight at 20° C. The resulting white, crystallineprecipitate was collected by vacuum filtration, washed with 2-3 L offresh γ-butyrolactone, 5 L of ethyl acetate and finally 5 L of hexanebefore drying in a forced air oven at 60° C. to afford 1.219 kg (96%) ofthe title compound: mp.=180-183° C.; IR exhibited combined ν(OH) andν(NH) bands, a distinct Amide I and an Amide II band consistent with thestructure of the title compound.

EXAMPLE 3

Methyl 2-Hydroxyoctanoate. Methyl 2-hydroxyoctanoate was obtainedfollowing the procedure of Example 1, except that 2-hydroxyoctanoic acidwas used in place of 2-hydroxydecanoic acid.

EXAMPLE 4

N,N'-Bis(2-hydroxyoctanoyl)cystamine,N,N'-Bis(2-hydroxydodecanoyl)cystaimine, N,N'-Bis(lactyl)cystamine andN,N'-Bis(salicylyl)cystamine. N,N'-Bis(2-hydroxyoctanoyl)cystamine,N,N'-Bis(2-hydroxydodecanoyl)cystamine, N,N'-Bis(lactyl)cystamine andN,N'-Bis(salicylyl)cystamine were obtained following the procedure ofExample 2, except that methyl 2-hydroxyoctanoate, methyl2-hydroxydodecanoate, methyl lactate and methyl salicylate,respectively, were used in place of methyl 2-hydroxydecanoate.

EXAMPLE 5

N-(2-Hydroxyoctanoyl)cysteamine. To a 1 L 1-neck round bottom reactionflask equipped with a teflon-coated stirrer bar and a reflux condenserwas added 600 mL of diethylene glycol monomethyl ether followed by 18.0g of N,N'-Bis(2-hydroxyoctanoyl)cystamine obtained from Example 4, 60.0g of NaBH₄ and 11.0 g of AlCl₃. The resulting mixture was allowed tostir at room temperature overnight. The reaction flask was placed in anice bath and to the reaction flask was gradually added, with vigorousstirring, 6M HCl until the vigorous evolution of gases ceased. Followingthe addition of the 6M HCl, the pH of the resulting aqueous phase was<3. The resulting mixture was extracted with three 700 mL portions ofethyl acetate. The ethyl acetate washings were combined, back-extractedwith three 700 mL portions of brine and three 700 mL portions of water,dried over Na₂ SO₄, and concentrated under reduced pressure (40° C. @100 mm Hg). The resulting semi-solid residue was triturated with hexane,and the resulting white solid was collected by vacuum filtration. Thewhite solid was washed with 25 mL of cold hexane and air dried. Thehexane mother liquor mixture was chilled to -78° C. and filtered toprovide additional solid which was added to the purified white solid,above, to afford the title compound in 68% combined yield: mp.=83-84°C.; IR ν(S-H) @2574 cm⁻¹ (weak); TLC R_(f) =0.6 (5% MeOH/CH₂ Cl₂),(R_(f) of N,N'-Bis(2-hydroxyoctanoyl)cystamine=0.5). The title compound,a microcrystalline white solid, was readily soluble in diethyl ether,ethyl acetate, ethanol and methanol, but was insoluble in either wateror cold hexane.

EXAMPLE 6

N-(2-Hydroxydecanoyl)cysteamine, N-(2-hydroxydodecanoyl)cysteamine,N-(lactyl)cysteamine and N-(salicylyl)cysteamine.N-(2-Hydroxydecanoyl)cysteamine, N-(2-hydroxydodecanoyl)cysteamine,N-(lactyl)cysteamine and N-(salicylyl)cysteamine were obtained followingthe procedure of Example 5, except thatN,N'-bis(2-hydroxydecanoyl)cystamine,N,N'-bis(2-hydroxydodecanoyl)cystamine, N,N'-bis(lactyl)cystamine andN,N'-bis(salicylyl)cystamine, respectively, were used in place ofN,N'-bis(2-hydroxyoctanoyl)cystamine.

EXAMPLE 7

Decrease in Skin Flakiness as Measured by Skin Desquamation. Fortyfemale subjects with dry hands were qualified for the study based onD-squame evaluation. In this test, cellophane tape was used to removestratum corneocytes from the skin's outer surface. The subjects did notuse moisturizers or any treatment formulation on their hands on the dayof testing and their baseline D-squame samples were collected. Thesubjects were randomly assigned to one of four treatment groups, withten subjects per group, and were given the test formulation to take homeand self-administer on the right hand only, twice a day in the morningafter washing and in the evening at least 15 minutes before bedtime forfour weeks. The left hand served as the untreated control site. Thesubjects were allowed to use the test formulation only and specificallylog its use in a daily diary provided. At the end of two and four weeks,the subjects returned for testing without administering the testformulation for at least 12 hours, and were reevaluated under the sameconditions.

Four D-squame discs were firmly and evenly pressed on each hand with ahand held uniform pressure device and removed by gently pulling awayfrom the skin. The D-squame discs were mounted on clear microscopeslides and labeled according to panelist name and visit. Desquamationwas evaluated from the D-squame discs via an image analyzer, which wasused to quantify the amount of stratum corneocytes which adhered to eachdisk. Skin evaluation, i.e., degree of desquamation, was carried outbefore treatment, and after two and four weeks of treatment.

An Optima image analyzer was used to evaluate skin flakiness. TheD-squame samples containing stratum corneocytes were placed under acamera mounted on top of a light table and each image was imported tothe image analyzer. The average Gray Value corresponding to the sampledensity was measured. The denser the sample, the higher the Gray Valuedifference, i.e., the higher the degree of desquamation and skinflakiness.

The test formulations and group assignments were as follows:

Group I: Formulation A

Group II: Formulation A less alphamix and less biolac, but with anadditional 10% by weight Octyldodecanol/Silica Mixture

Group III: Formulation A less alphamix and less biolac but with anadditional 2% by weight N,N'-Bis(salicylyl)cystamine

Group IV: Formulation A less alphamix and less biolac but with anadditional 10% by weight N,N'-Bis(lactyl)cystamine as a 10% aqueoussolution

Formulation A

    ______________________________________                                        Formulatio A                                                                  Component             Percent                                                 ______________________________________                                        Deionized Water       66.35                                                   Phenoxyethanol        0.063                                                   Methyl Paraben        0.018                                                   Imidazolidinyl Urea   0.300                                                   Sodium Hyaluronate    0.090                                                   Water/Guanine/Isopropyl Alcohol/                                                                    1.000                                                   Methylcellulose Mixture                                                       Alphamix.sup.1        2.000                                                   Biolac.sup.2          2.000                                                   Tetrahydroxypropyl Ethylenediamine                                                                  0.500                                                   Polysorbate 40        2.500                                                   Silicone 200.sup.3    5.000                                                   Polyacrylamide/C.sub.13 -C.sub.14 Isoparaffin/                                                      5.000                                                   Laureth-7 Mixture                                                             Fragrance             0.075                                                   FD & C Yellow No. 5 (1% aq. solution)                                                               0.026                                                   FD & C Yellow No. 6 (1% aq. solution)                                                               0.052                                                   FD & C Red No. 40 (0.5% aq. solution)                                                               0.026                                                   Cyclomethicone        15.00                                                   ______________________________________                                         .sup.1 35% hydroxydecanoic acid                                               3.8% hydroxyoctanoic acid                                                     61.2% butylene glycol                                                         .sup.2 Biolac consists of 28-35% lactic acid and 65-72% inert ingredients     .sup.3 Dimethicone                                                       

As shown below in Table 1, the results indicate that following two andfour weeks of treatment, skin flakiness decreased by 17% and 38%,respectively, among Group IV subjects, i.e., those who administered in aformulation comprising N,N'-bis(lactyl)cystamine. In addition, skinflakiness decreased by 16% and 27%, respectively, among Group IIIsubjects, i.e., those who administered a formulation comprisingN,N'-bis(salicylyl)cystamine. These results are clearly superior tothose obtained by Group I and Group II subjects, i.e., those whoadministered formulations that did not comprise an amide or bis-amide ofthe present invention. Thus, the results shown in Table 1 clealy showthat illustrative bis-amides of the present invention are useful fortreating an abnormal condition of the skin.

                  TABLE 1                                                         ______________________________________                                                         % Decrease in Skin Flakiness                                                  2 Weeks  4 Weeks                                             ______________________________________                                        Group I treated arm    -21.08     -36.09                                              untreated arm (control)                                                                      -43.72     -63.21                                              treated - untreated                                                                          22.64      27.12                                       Group II                                                                              treated arm    -8.74      -29.30                                              untreated arm (control)                                                                      -16.74     -36.97                                              treated - untreated                                                                          8.00       7.67                                        Group III                                                                             treated arm    -1.69      40.10                                               untreated arm (control)                                                                      -17.96     13.38                                               treated - untreated                                                                          16.27      26.72                                       Group IV                                                                              treated arm    4.13       53.25                                               untreated arm (control)                                                                      -13.23     14.77                                               treated - untreated                                                                          17.36      38.48                                       ______________________________________                                    

EXAMPLE 8

Decrease in Skin Flakiness Following the Application of a FormulationContaining 1% N-(lactyl) cysteamine Compared to Other Test Formulations.Following the protocol described in Example 7, above, skin flakiness wasassessed from subjects who administered various test formulations, shownbelow in Table 2, over a two and four week period. As can be seen fromTable 2, after 2 weeks of administration, the test formulationcomprising 1% N-(lactyl)cysteamine resulted in a 34.9% decrease in skinflakiness, the largest decrease in skin flakiness among all theformulations tested over 2 weeks. Thus, the results shown in Table 2clearly demonstrate the utility of the amides of the present invention.

                  TABLE 2                                                         ______________________________________                                                        % Decrease in Skin Flakiness                                                  2 Weeks   4 Weeks                                             ______________________________________                                        1% N-(lactyl)cysteamine                                                                         34.9        21.1                                            Formulation A     23.0        29.0                                            Formulation A     31.4        30.6                                            Formulation A     32.8        36.6                                            Formulation A (seasonal variation)                                                              13.5        25.0                                            0.5% dihydroxysebacic acid                                                                      9.6         24.3                                            1.4% α-hydroxylauric acid (pH 4.04)                                                       27.6        28.7                                            5.28% Phytic acid 35.6        19.9                                            1% Mandelic acid  38.2        21.4                                            1% Ceramide 6b C10.sup.1                                                                        33.7        24.0                                            plus 0.1% Ceramide 6c C8.sup.2                                                0.8% Salicylic acid (47.1, 1 week)                                                              21.0        n/a                                             10% Salisomes.sup.3                                                           pH 3.89           18.0        26.4                                            pH 7.0            -1.5         7.6                                            ______________________________________                                         .sup.1 N(2-hydroxydecanoyl)phytosphingosine                                   .sup.2 N(2-hydroxyoctanoyl)phytosphingosine                                   .sup.3 liposomes containing salicylic acid (see EP 616 799)              

EXAMPLES 9-12 Pharmaceutical or Cosmetic Compositions EXAMPLE 9

Butylene glycol and water are mixed and dissolved in alcohol. Theresultant vehicle mixture and a compound of formula I or formula IV, ora mixture thereof are mixed and dissolved. The resultant formulation isa tincture.

EXAMPLE 10

In this example a topical cream is prepared by first mixing and meltingsqualane, stearyl alcohol NF, cetyl alcohol polyethylene glycol cetylether, mineral oil NF and petrolatum USP, at 70° C. A second mixture isformed by mixing and dissolving methyl paraben NF and propyl paraben NFin water, at 70° C. The second mixture is slowly added to and mixed withthe first mixture to form an emulsion. A compound of formula I orformula IV, or a mixture thereof is dispersed in the resultant emulsionat 50° C. The resultant composition is slowly cooled with mixing untilthe composition reaches room temperatures.

EXAMPLE 11

In this example a topical ointment is prepared. As a first step,glyceryl monostearate is mixed and melted in petrolatum USP at 70° C. Asa second step, A compound of formula I or formula IV, or a mixturethereof is mixed and dissolved in butylene glycol at 70° C. Theresultant composition of step 2 is slowly added to the resultantcomposition of step 1, with mixing. This mixture is then cooled to itscongealing point with mixing and then cooled to room temperature withoutmixing.

EXAMPLE 12

In this example a topical gel is prepared. As a first step, hydroxypropyl cellulose is hydrated and dissolved into water. As a second step,A compound of formula I or formula IV, or a mixture thereof, butyleneglycol and PPG-12-Buteth-16 are dissolved in alcohol. Slowly theresultant mixture of step 2 is added into the resultant mixture of step1 with mixing until a gel forms.

                                      TABLE 3                                     __________________________________________________________________________    Amide and/or Bis-Amide Formulations                                                          Example 9                                                                          Example 10                                                                           Example 11                                                                          Example 12                                                  Topical                                                                            Topical                                                                              Topical                                                                             Topical                                                     Tincture                                                                           Cream/Lotion                                                                         Ointment                                                                            Gel                                          Ingredients    % w/w                                                                              % w/w  % w/w % w/w                                        __________________________________________________________________________      Compound of formula I,                                                                     1.0  1.0    1.0   1.0                                            formula IV, or a mixture                                                      thereof                                                                       Methyl Paraben NF                                                                          --    .01   --    --                                             Propyl Paraben NF                                                                          --    .01   --    --                                             Hydroxy Propyl Cellulose                                                                   --   --     --    1.0                                            (note 1)                                                                      PPG-12-Buteth-16 (note 2)                                                                  --   --     --    2.0                                            Squalane (note 3)                                                                          --   2.0    --    --                                             Glyceryl Monosteanate NF                                                                   --   --     2.0   --                                             Stearyl Alcohol NF                                                                         --   2.8    --    --                                             Cetyl Alcohol NF                                                                           --   4.2    --    --                                           10.                                                                             Polyethylene Glycol                                                                        --   5.0    --    --                                             Cetyl Ether (note 4)                                                          Mineral Oil NF                                                                             --   5.0    --    --                                             Butylene Glycol                                                                            4.0  --     12.0  4.0                                            Petrolatum USP                                                                             --   5.4    85.0  --                                             Alcohol (note 5)                                                                           89.0 --     --    47.0                                           Water        6.0  74.4   --    45.0                                                        100.0                                                                              100.0  100.0 100.0                                        __________________________________________________________________________     Notes:                                                                        (1) available under the trademark Klucel ® from Hercules                  (2) available under the trademark Ucon ® fluid 50 HB from Union           Carbide                                                                       (3) available under the trademark Robane  ® from Robeco                   (4) available under the trademark Brij 58 ® from ICI                      (5) contains 95% ethanol and 5% water                                    

EXAMPLE 13

To examine the effect of the amides and bis-amides of the presentinvention on the skin, stratum corneum is used as a model to determinethe degree in which the amides and bis-amides of the present inventioneffectively treat dry skin by increasing the extensibility thereof.Stratum corneum samples are first equilibrated to 44% relative humidity(RH) by suspending the samples over a saturated salt solution ofpotassium carbonate. After equilibration, the stratum corneum samplesare extended by 2% of their original length at 20 mm/min using a linearextensometer. The amount of force required to extend the sample iscomputed and the information displayed as a force extension graph on apersonal computer. The initial slope of the curve in the Hookean regionis then used as an indicator of the integrity of the stratum corneum(gram-force/100% extension). 50 μl of the amide or bis-amide to betested is then applied to the external surface of five pieces of stratumcorneum samples and rubbed in with 20 strokes of a gloved finger. Thesamples are then equilibrated to 80% RH by suspending over a saturatedsalt solution of ammonium sulfate in humidity chambers and thenincubated at this humidity for three hours. The samples are thenreequilibrated to 44% RH and after conditioning, restretched to 2%extension. Results are then expressed as extensibility ratios ofbefore/after treatment. The same test is run for 4% extension.

EXAMPLE 14

To the half an area of the face, neck, forearm, back or buttocks of eachmember of a panel of approximately 50 healthy volunteers is administereda composition comprising 0.01-5 wt. % of a compound of formula I orformula IV or mixture thereof and to the other half an area isadministered a control composition. Applications are made once to 4times daily for up to six months or more depending upon the condition tobe treated. Panelists are assessed by expert assessors for overallimprovement in the condition to be treated or the improvement in thetexture and appearance of the skin.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodimentswhich are functionally equivalent are within the scope of thisinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art and are intended to fall within the appended claims.

A number of references have been cited and the entire disclosures ofwhich are incorporated herein by reference.

What is claimed is:
 1. A compound of formula I:

    R--NH--Z--SH                                               (I)

or a pharmaceutically or cosmetically acceptable salt thereof, wherein: R is (A)(A)C(OH)--C(O)--; wherein each A is independently selected from the group consisting of hydrogen, phenyl and a C₁ -C₂₂ alkyl or alkenyl group, said C₁ -C₂₂ alkyl or alkenyl group being optionally substituted with one or more C₁ -C₄ alkyl groups, phenyl, or halogen groups, said phenyl being optionally substituted with one or more C₁ -C₄ alkyl, halogen, hydroxyl groups, or methoxyl groups; and Z is selected from the group consisting of C₂ -C₁₂ alky, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl.
 2. The compound of claim 1, wherein R is selected from the group consisting of 2-hydroxyethanoyl; 2-hydroxypropanoyl; 2-methyl-2-hydroxypropanoyl; 2-hydroxybutanoyl; 2-hydroxypentanoyl; 2-hydroxynonanoyl; 2-hydroxydecanoyl; 2-hydroxyoctanoyl; 2-hydroxydodecanoyl; 2-hydroxytetradecanoyl; 2-hydroxyhexadecanoyl; 2-hydroxyoctadecanoyl; 2-hydroxyeicosanoyl; 2-hydroxyphenyl-2-hydroxyethanoyl; 2,2-diphenyl-2-hydroxyethanoyl; 3-phenyl-2-hydroxypropanoyl; 2-phenyl-2-methyl-2-hydroxyethanoyl; 2-(4'-chlorophenyl)-2-hydroxyethanoyl; 2-(4'-hydroxy-3'methoxyphenyl)-2-hydroxyethanoyl; 3-(2'-hydroxyphenyl)-2-hydroxypropanoyl; 3-(4'-hydroxyphenyl)-2-hydroxypropanoyl; and 2-(3', 4'-dihydroxyphenyl)-2-hydroxyethanoyl; andZ is C₂ -C₆ alkyl.
 3. The compound of claim 1, wherein said compound is selected from the group consisting of:N-(lactyl)cysteamine; N-(2-hydroxyoctanoyl)cysteamine; N-(2-hydroxydecanoyl)cysteamine; and N-(2-hydroxydodecanoyl)cysteamine, or a pharmaceutically or cosmetically acceptable salt thereof.
 4. A composition for treating an abnormal biological skin condition or disease, said composition comprising a pharmaceutically or cosmetically acceptable vehicle and a compound of formula I:

    R--NH--Z--SH                                               (I)

or a pharmaceutically or cosmetically acceptable salt thereof, wherein: R is selected from the group consisting of (A)(A)C(OH)--C(O)-- and 2-(HO)C₆ H₄ C(O)--; wherein each A is independently selected from the group consisting of hydrogen, phenyl and a C₁ -C₂₂ alkyl or alkenyl group, said C₁ -C₂₂ alkyl or alkenyl group being optionally substituted with one or more C₁ -C₄ alkyl groups, phenyl, or halogen groups, said phenyl being optionally substituted with one or more C₁ -C₄ alkyl, halogen, hydroxyl groups or methoxyl groups; and Z is selected from the group consisting of C₂ -C₁₂ alkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl.
 5. The composition of claim 4, wherein said compound is selected from the group consisting of:N-(salicylyl)cysteamine; N-(lactyl)cysteamine; N-(2-hydroxyoctanoyl)cysteamine; N-(2-hydroxydecanoyl)cysteamine; and N-(2-hydroxydodecanoyl)cysteamine, or a pharmaceutically or cosmetically acceptable salt thereof.
 6. The composition of claim 4 wherein said compound is present in an amount of about 0.01 to about 5 wt. % of the composition.
 7. The composition of claim 6 wherein said compound is present in an amount of about 0.05 to about 1.0 wt. % of the composition.
 8. The composition of claim 4 wherein said vehicle is selected from the group consisting of lotions, tinctures, creams, emulsions, mousses, sprays, foams, powders, gels and ointments.
 9. The composition of claim 4 wherein said composition is a topical composition.
 10. The composition of claim 4, further comprising one or more alpha- or beta-hydroxyacids selected from the group consisting of lactic acid, glycolic acid, citric acid, alpha-hydroxyoctanoic acid, alpha-hydroxydecanoic acid, alpha-hydroxylauric acid, tartaric acid, glucouronic acid, galactouronic acid, alpha-hydroxybutyric acid, alpha-hydroxyisobutyric acid, malic acid, mandelic acid, pyruvic acid, tartronic acid, and salicylic acid, and ester, thioester, amide and lactone derivatives thereof.
 11. A method for treating an abnormal biological skin condition or disease selected from the group consisting of dry skin, severe dry skin, dandruff acne, keratoses, psoriasis, eczema, skin flakiness, pruritus, age spots, lentigines, melasmas, coarse wrinkles, fine wrinkles, warts, blemished skin, hyperpigmented skin, hyperkeratotic skin, inflammatory dermatoses, skin in need of cleansers and skin atrophy, in a patient in need of such treatment, which comprises topically administering to the patient on the area of skin having said condition or disease a composition comprising a pharmaceutically or cosmetically acceptable vehicle and a compound of formula I:

    R--NH--Z--SH                                               (I)

or a pharmaceutically or cosmetically acceptable salt thereof, wherein: R is selected from the group consisting of (A)(A)C(OH)--C(O)-- and 2-(HO)C₆ H₄ C(O)--; wherein each A is independently selected from the group consisting of hydrogen, phenyl and a C₁ -C₂₂ alkyl or alkenyl group, said C₁ -C₂₂ alkyl or alkenyl group being optionally substituted with one or more C₁ -C₄ alkyl groups, phenyl, halogen or hydroxyl groups, said phenyl being optionally substituted with one or more C₁ -C₄ alkyl, halogen, hydroxyl groups or methoxyl groups; and Z is selected from the group consisting of C₂ -C₁₂ alkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl.
 12. The method of claim 11, wherein said compound is selected from the group consisting of:N-(salicylyl)cysteamine; N-(lactyl)cysteamine; N-(2-hydroxyoctanoyl)cysteamine; N-(2-hydroxydecanoyl)cysteamine; and N-(2-hydroxydodecanoyl)cysteamine, or a pharmaceutically or cosmetically acceptable salt thereof.
 13. The method of claim 11 wherein said compound is present in an amount of about 0.01 to about 5 wt. % of the composition.
 14. The method of claim 13 wherein said compound is present in an amount of about 0.05 to about 1.0 wt. % of the composition.
 15. The method of claim 11 wherein said vehicle is selected from the group consisting of lotions, tinctures, creams, emulsions, mousses, sprays, foams, powders, gels and ointments.
 16. The method of claim 11, wherein the composition further comprises one or more alpha- or beta-hydroxyacids selected from the group consisting of lactic acid, glycolic acid, citric acid, alpha-hydroxyoctanoic acid, alpha-hydroxydecanoic acid, alpha-hydroxylauric acid,, tartaric acid, glucouronic acid, galactouronic acid, alpha-hydroxybutyric acid, alpha-hydroxyisobutyric acid, malic acid,, mandelic acid, pyruvic acid, tartronic acid, and salicylic acid, and ester, thioester, amide and lactone derivatives thereof. 